Bedside personalized methods based on electrical impedance tomography or respiratory mechanics to set PEEP in ARDS and recruitment-to-inflation ratio: a physiologic study

Background Various Positive End-Expiratory Pressure (PEEP) titration strategies have been proposed to optimize ventilation in patients with acute respiratory distress syndrome (ARDS). We aimed to compare PEEP titration strategies based on electrical impedance tomography (EIT) to methods derived from respiratory system mechanics with or without esophageal pressure measurements, in terms of PEEP levels and association with recruitability. Methods Nineteen patients with ARDS were enrolled. Recruitability was assessed by the estimated Recruitment-to-Inflation ratio (R/Iest) between PEEP 15 and 5 cmH2O. Then, a decremental PEEP trial from PEEP 20 to 5 cmH2O was performed. PEEP levels determined by the following strategies were studied: (1) plateau pressure 28–30 cmH2O (Express), (2) minimal positive expiratory transpulmonary pressure (Positive PLe), (3) center of ventilation closest to 0.5 (CoV) and (4) intersection of the EIT-based overdistension and lung collapse curves (Crossing Point). In addition, the PEEP levels determined by the Crossing Point strategy were assessed using different PEEP ranges during the decremental PEEP trial. Results Express and CoV strategies led to higher PEEP levels than the Positive PLe and Crossing Point ones (17 [14–17], 20 [17–20], 8 [5–11], 10 [8–11] respectively, p < 0.001). For each strategy, there was no significant association between the optimal PEEP level and R/Iest (Crossing Point: r2 = 0.073, p = 0.263; CoV: r2 < 0.001, p = 0.941; Express: r2 < 0.001, p = 0.920; Positive PLe: r2 = 0.037, p = 0.461). The PEEP level obtained with the Crossing Point strategy was impacted by the PEEP range used during the decremental PEEP trial. Conclusions CoV and Express strategies led to higher PEEP levels than the Crossing Point and Positive PLe strategies. Optimal PEEP levels proposed by these four methods were not associated with recruitability. Recruitability should be specifically assessed in ARDS patients to optimize PEEP titration. Supplementary Information The online version contains supplementary material available at 10.1186/s13613-023-01228-4.


Introduction
Acute respiratory distress syndrome (ARDS) is a major cause of mortality and morbidity in critically ill patients [1].It is well established that a so-called lung protective ventilation strategy allows to improve patients' outcomes [2].This strategy is based on limited plateau pressure and tidal volume and adjusted positive end-expiratory pressure (PEEP) levels [2,3].There is, however, an important heterogeneity in terms of response to PEEP in patients with ARDS [4].The concept of recruitability has been proposed to predict this response, in terms of "reopened" volume of flooded alveoli [4,5].
Numerous PEEP titration strategies based on oxygenation, respiratory system mechanics or esophageal pressure measurements have been proposed, but none has been shown to be superior to any other [6][7][8].These disappointing results might be explained by the inability of these PEEP titration strategies to deliver higher PEEP levels to patients with higher recruitability.Electrical impedance tomography (EIT) is an innovative technique using thoracic impedance to provide a real-time imaging of the distribution of gas in the lungs during ventilation [9,10].This allows the assessment of regional lung ventilation, including the re-opening of previously collapsed lung regions [11].Different PEEP titration strategies have thus been proposed, based on the assessment with EIT of gas volume distribution between dependent and non-dependent regions of the lungs [12] and of the change in the amount of lung collapse and overdistension in response to an increase in PEEP [13].The physiological effects of these EIT-based PEEP titration strategies are, however, poorly known.The interaction between these titration methods and recruitability has never been assessed.
This study hypothesis was that EIT-based strategies may lead to different PEEP levels from previously described bedside titration methods and allow to apply higher PEEP levels in patients with higher recruitability.In this exploratory, physiological study, we aimed to compare the PEEP levels determined by two EIT-based PEEP titration strategies and two respiratory mechanics-based methods and to assess the relation between these determined PEEP levels and the recruitability in patients with moderate to severe ARDS.

Study population
Nineteen adult patients, admitted to the Medical ICU of the University Hospital of Angers, France, from December 2019 to April 2020 were enrolled within 24 h after the diagnosis of ARDS defined according to the Berlin criteria.Ten patients with a COVID-19 associated ARDS (C-ARDS) have been included in a previously published study [14].
Ethics approval was obtained from the appropriate legal and ethical authorities (ethics committee of the University Hospital of Angers #2023-42).As the study reports data routinely acquired in usual care, signed informed consent was waived, according to local legislation.

Patients' installation and settings
Patients were deeply sedated by Midazolam and Fentanyl and paralyzed by continuous infusion of Cisatracurium.They were positioned in semi-recumbent position and ventilated in volume assist control mode using a Carescape R860 ventilator (General Electrics Healthcare ® , Madison, WI, USA).The following settings were applied to all patients: tidal volume 6 mL.kg −1 predicted body weight (PBW), respiratory rate set by the attending physician adjusted to maintain arterial pH above 7.30 (up to 35 min −1 ), FiO 2 to obtain SpO 2 > 94%.
EIT tracings were continuously recorded using a Pulmovista (Draeger ® , Lubeck, Germany) device.The tomography belt was positioned under armpits, between the third and the fifth intercostal space [9].The anti-bedsore device mattress was turned off during the measurements to avoid interferences.
Esophageal pressure measurements were obtained with a specific nasogastric feeding tube equipped with an esophageal balloon (NutriVent ® , Sidam, San Giacomo Roncole, Italy) connected to the ventilator (see the Additional file 1 for further information).
During all the study procedures, ventilator tracings including esophageal pressure measurements, EIT signals (ventilation distribution and lung volumes) were continuously recorded (further information on computed data are available in the Additional file 1: Table S1).

Study protocol
Two distinct steps were consecutively conducted.The whole study protocol is summarized in the Additional file 1: Fig. S1.

Exploration of response to PEEP
PEEP level of 15, then 5 cm H 2 O was applied for 20 min.At the end of each period, inspiratory and expiratory pauses were performed, and arterial blood gases were obtained.
In addition, at PEEP 5 cmH 2 O, a low flow pressure volume curve was performed to detect a complete airway closure and measure airway opening pressure (AOP) [15].

Decremental PEEP trial
PEEP level was increased at 20 cmH 2 O then was progressively decreased by steps of 3 cmH 2 O every 3 min, until PEEP reached 5 cmH 2 O. Inspiratory and expiratory pauses were performed at the end of each step.The dynamic course of Center of Ventilation (CoV, the percentage of ventilation reaching the dorsal half of the lung), Pplat and expiratory transpulmonary pressure (P L e, difference between total PEEP and expiratory esophageal pressure) across the different PEEP levels were computed offline.EIT tracings allowed the estimation of lung ventilation distribution to assess the Center of Ventilation (CoV), and the reconstruction of Overdistension (OD) and Lung Collapse (LC) (see Additional file 1).

Evaluation of recruitability
The recruitability was evaluated during the first phase with the estimated Recruitment-to-Inflation Ratio (R/ I est ), computed from an EIT-based measurement of the change in end-expiratory lung volume (ΔEELV EIT ), as previously described [19].
ΔEELV EIT was calculated by measuring the end-expiratory impedance gap between 15 and 5 cmH 2 O, corrected by the volume-impedance ratio [19].In a sample of 9 patients from the present cohort, ΔEELV EIT correlated well with ΔEELV measured by the single breath method (rho 0.716, p = 0.037, Additional file 1: Fig. S2).
The recruited volume (V REC ) was computed as the difference between ΔEELV EIT and the inflated volume related to the lung compliance at low PEEP, as follows: [20].ΔPEEP was the difference between the two PEEP levels (i.e., 15-5 = 10 cm H 2 O) or between the high PEEP level and the AOP in presence of complete airway closure at PEEP 5 cmH 2 O [5].Recruited compliance (C REC ) was computed as V REC /ΔPEEP.R/I est was computed as the ratio between C REC and C RS -PEEP5 [5].
To normalize the recruited volume on each patient weight, V REC /PBW was also calculated.
V REC , as V REC /PBW, could also be computed at each PEEP level from 5 cmH 2 O, by changing the ΔPEEP value by the following: PEEP studied -5 (or AOP if it reached a value above 5 cmH 2 O), in cmH 2 O.

Evaluation of response to PEEP in terms of oxygenation and compliance
During the second study step, response on oxygenation (ΔPaO 2 /FiO 2 ) was calculated as the difference between PaO 2 /FiO 2 at PEEP 15 and 5 cmH 2 O, divided by the PaO 2 /FiO 2 at 5 cmH 2 O.The same approach was used to assess the response on respiratory system compliance (ΔC RS ).

Statistical analysis
Data are expressed in number (percentage) or median [first-third quartile].
Patients were also pooled in groups according to: (1) measured R/I est ratio, higher R/I est and lower R/I est groups were selected based on the median R/I est value; (2) ΔPaO 2 /FiO2, also based on the cohort median value; (3) ΔC RS , also based on the cohort median value; (4) COVID associated ARDS vs. non-COVID ARDS.
Statistical comparisons were performed using a Mann-Whitney U-test for simple comparisons.For multiples comparisons, Friedman test or ANOVA were performed as appropriate; Bonferroni's or Tukey's correction were, respectively, applied to assess differences between two methods.Correlations between PEEP levels computed by the tested strategies and different recruitability and response to PEEP markers were performed using Spearman's correlations.
All tests were performed with a type I error set at 0.05.The statistical analysis was performed using Prism (GraphPad Software v9.0, La Jolla, CA, USA).

Patients' characteristics
Baseline characteristics at inclusion of the 19 patients are summarized in the Table 1.
Eleven patients (58%) died before day 28.Esophageal pressure data were missing for one patient, due to a technical limitation.

PEEP levels determined according to the different titration strategies
No adverse event was reported during the decremental PEEP trial.
The different variables of interest assessed to define optimal PEEP levels according to the different titration strategies during the decremental PEEP trial are described in Fig. 1.
In the whole cohort, the four PEEP titration strategies led to different PEEP levels (Fig. 2).
We observed no difference in the optimal PEEP levels between patients with C-ARDS and patients with ARDS of other etiologies in all the tested titration strategies (Additional file 1: Fig. S3).
There was no correlation between R/I est and the optimal PEEP levels computed by the different methods (Fig. 3).Similar results were obtained with V REC/ PBW (Additional file 1: Fig. S4).The comparison of ΔCollapse 20-5 to the different optimal PEEP levels led to similar results, except for the Crossing Point method (Additional file 1: Fig. S5).
The determined PEEP levels did not differ between the Higher and Lower R/I est ratio groups in all the tested PEEP titration strategies (Additional file 1: Fig. S6).

Respiratory mechanics associated with each PEEP titration strategy
The different PEEP titration strategies led to differences in respiratory mechanics (Table 2).The CoV and Express strategies led to improved alveolar recruitment markers, with higher overdistention and lower compliance than the Crossing Point and Positive P L e methods.

Changes in oxygenation and respiratory system compliance in response to PEEP increase
Changes in oxygenation and C RS after a PEEP increase from 5 to 15 cmH 2 O also covered a wide range: median ΔPaO 2 /FiO 2 was 18.3 [− 3.8-37.1]% and median ΔC RS − 5.6 [− 31.9-14.9]%.
Optimal PEEP levels defined by each strategy were not different between the patients for whom oxygenation significantly increased after an increase in PEEP and those for whom oxygenation did not increase (Additional file 1: Fig. S7A).Similar results were obtained by analyzing changes in C RS (Additional file 1: Fig. S7B).

Impact of the PEEP range of the decremental PEEP trial on Crossing Point computation
Significant differences in PEEP levels determined according to the Crossing Point method were observed when the range of PEEP considered for the decremental PEEP trial and OD and LC curves reconstruction was modified (Fig. 4 and Additional file 1: Fig. S9).

Discussion
The main findings of this study could be summarized as follows: (1) the four studied strategies lead to different optimal PEEP values, with CoV and Express strategies promoting similarly higher levels than the Crossing Point and Positive P L e ones.(2) There was no association between the PEEP levels obtained with these four different PEEP titration strategies and the recruitability assessed by R/I est .(3) Both CoV and Express associated PEEP levels are characterized by improved recruitment, but also increased overdistension and airway pressures; Crossing Point and positive P L e methods promote minimal overdistension and increased C RS but have a lower impact on alveolar recruitment.(4) PEEP levels determined by the Crossing Point strategy depends on the PEEP range studied during the decremental PEEP trial.

Association between lung recruitability and "optimal" PEEP levels
In the present series, optimal PEEP levels differed between the four tested strategies and were not related to R/I est ratio.These results are consistent with other studies evaluating different EIT and esophageal pressure-based PEEP titration strategies [21][22][23].In a physiological study using CT-scan to evaluate lung recruitability, neither the Express method nor the strategies based on esophageal pressure led to PEEP levels associated with recruitability [21].Of note, patients with PaO 2 /FiO 2 ratio between 200 and 300 mm Hg were included in this work.In another recent series in patients with C-ARDS, Perier et al. found no difference in PEEP levels determined by the Crossing Point method, in two subgroups defined according to lung recruitability assessed by the R/I ratio [22].Similarly, Su et al. also reported an absence of correlation between the recruited volume and the optimal PEEP level measured by the Crossing Point method [23].Interestingly, in another group of patients with severe ARDS, this strategy led to a better short-term mortality than a method based on the pressure-volume curve (PEEP set 2 cmH 2 O above the lower inflection point) [24].However, in a recent large cohort characterized by a large heterogeneity among patients, there was an association between recruitability (measured by the ΔCollapse 20-5 method using EIT), and the optimal PEEP level computed by the Crossing Point method, but also with ventilation homogeneity [18].Importantly, in all these studies, the Crossing Point method allowed to set high PEEP levels, in populations characterized by a very high recruitability.Elsewhere, in a population of post-surgical non-ARDS patients, the optimal PEEP level obtained with the CoV strategy was reached at the highest PEEP levels, suggesting a direct impact of PEEP on lung volume redistribution, even in patients without ARDS (i.e.not characterized by a high recruitability, albeit it was not assessed in this study) [25].
Importantly, to the best of our knowledge, our study is the first to compare respiratory mechanics, esophageal pressure and two distinct EIT-based titration strategies.The lack of association between lung recruitability and "optimal" PEEP levels observed in our study may contribute to explain the failure of large randomized controlled trials assessing PEEP titration strategies in ARDS [6][7][8].

Towards a personalized PEEP titration strategy?
Among the four PEEP titration strategies tested in the present study, the rationale of CoV and Express strategies is mainly to target homogeneous ventilation and maximal recruitment, while Crossing Point and positive P L e strategies aim to combine "acceptable" recruitment and limited risk of overdistention during inspiration.Two recent studies compared the "silent spaces" strategy (aiming to reduce the total amount of unventilated lung volume) to strategies based on respiratory mechanics [26] or PEEP-FiO 2 tables [27].In these works, the "silent spaces" strategy was associated with higher PEEP levels, with improved recruitment, ventilation homogeneity and gas exchange.
Of note, the strategies based on lung homogeneity (CoV) and respiratory system mechanics (Express) led to higher PEEP levels than those based on the intersection of LC and OD curves and positive P L e strategies.Highly recruitable patients may benefit from strategies promoting recruitment, whereas minimal overdistension methods may be more appropriate for poorly recruitable patients.These results may thus be an incentive to specifically assess recruitability rather than systematically use any PEEP titration strategy.The choice of the optimal titration strategy may be discussed according to the most relevant awaited physiological benefit for the considered patient.

Impact of PEEP range using the Crossing Point strategy
Our study shows that the PEEP level obtained with the Crossing Point strategy is impacted by the PEEP range used during the decremental PEEP trial.In patients with ARDS, four physiological studies aimed to study PEEP titration using Crossing Point method [17,22,28,29].In two series, optimal PEEP levels assessed by the Crossing Point method were higher than those determined by the same strategy in our study [17,29].This difference may be explained by the use of higher maximal PEEP levels during the decremental PEEP trial (from 40 to 5 cm H 2 O and from "at least" 24 to 10 cm H 2 O, respectively) [17,29].In the two studies using PEEP ranges close to the one used in our study (from 20 to 0 cm H 2 O, and from 6 to 18 cm H 2 O, respectively), optimal PEEP determined using the Crossing Point method were consistent with the levels observed in our cohort [22,28].
These differences could be explained by the method of computation of lung collapse and overdistension, including the difference between the maximal compliance and the current compliance for each pixel at a given PEEP level, the wider the interval of PEEP levels studied, the higher the maximal compliance in some pixels [30].This effect is illustrated in the Additional file 1: Fig. S8.

Study limitations
There are some important limitations to this study: (1) the number of included patients is relatively small.(2) The study population is heterogeneous, with a large distribution of PaO 2 /FiO 2 ratio at enrollment.In addition, more than half of the patients included in this study had a diagnosis of C-ARDS.No interaction between the ARDS etiology (i.e., COVID-19 vs. non-COVID-19) and determined PEEP levels was, however, observed.And differences in respiratory mechanics between C-ARDS and ARDS of other etiologies have been shown to be slight or non-existent and a large variety of phenotypes has been described in each group [31,32].(3) Respiratory system compliance was markedly high in our cohort, in comparison with other studies [1,6,7].These values could be explained by the enrollment at the very early course of the disease [31].(4) One could criticize the use of an EIT-based method to assess the R/I ratio.The V REC computation based on EIT provides, however, results closely (5) Some physiologic effects may have not been perfectly controlled during the study.In particular, no recruitment maneuver with PEEP higher than 20 cmH 2 O was performed prior to the PEEP trial.And neither cardiac output nor mixed or central venous oxygen saturation was assessed in the study.However, no patient underwent any hemodynamic failure related to high PEEP levels during the PEEP trial.Finally, the shortterm impact of the experiment on respiratory mechanics or gas exchange was not assessed.

Conclusions
In this population of patients with ARDS, the CoV and Express strategies led to higher PEEP levels than the Crossing Point and Positive P L e strategy.Optimal PEEP levels proposed by these four methods were not associated with recruitability.Hence, recruitability should be specifically assessed in ARDS patients to optimize PEEP titration.The optimal method to set PEEP according to the R/I ratio remains to be determined.
and Getinge Group, outside this work.The other authors have no conflict of interest to declare.

Fig. 2 Fig. 3
Fig. 2 Positive End-Expiratory Pressure (PEEP) levels determined by the different titration strategies.CoV Center of Ventilation, Crossing Point Lung Collapse and Overdistension curves crossing point.*p < 0.05

Table 1
Patients' characteristics at baseline AOP Airway Opening Pressure, ARDS Acute Respiratory Distress Syndrome, BMI Body Mass Index, C CW chest wall compliance, C RS respiratory system compliance, E L /E RS lung elastance to respiratory system elastance ratio, FiO 2 Fraction of inspired oxygen, PaCO 2 Partial pressure of arterial carbon dioxide, PaO 2 Partial pressure of arterial oxygen, PEEPtot total Positive End-Expiratory Pressure, PLR Potential for Lung Recruitment, SAPS II Simplified Acute Physiology Score II